JPS585195B2 - How to prepare for the construction process - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION Prostaglandins are a group of natural substances isolated from various animal tissues.

In mammals, prostaglandins have been implicated in many physiological effects.

Natural prostaglandins generally have a carbon substructure of 20 carbon atoms and are distinguished by a higher or lower content of hydroxyl groups or double bonds in the cyclopenkune ring (prostaglandin Regarding structure and action, especially M.F.
``The Prostaglandins'' by N.F. Cuthbert, Pharmacological and Therapeutic Advances (William)
He inemann Medica l Boo
ksLid, London) 1973).

The synthesis of non-natural brostanic acid analogs, which differ from natural brostanic acid in a number of pharmacological actions, has gained increasing importance in recent years.

The present invention relates to novel, non-naturally occurring brostanic acid analogs having the following general formula I and their physiologically acceptable salts with inorganic or organic bases.

[In the formula, R1 and R2 are jointly oxygen or each hydrogen or hydroxyl group, and in this case R1 and R2 are different], U is a (CH2)m- group (m means 0 to 5) ), (R and R4 are the same or different and mean hydrogen or alkyl having 1 to 5 carbon atoms), or -, S=, S- group (wherein R3 and R4 are the same hydrogen or alkyl having 1 to 5 carbon atoms, where ■ and W are each a single bond and X=(CH2)1
~． , both cannot be hydrogen at the same time), and ■ is a single bond, oxygen, or a formula (in which R
3 and R4 are the same or different, meaning hydrogen or alkyl with 1 to 5 carbon atoms), and W is a single bond or a residue of the formula (in which R5 and R6 are are the same or different, meaning hydrogen or alkyl having 1 to 5 carbon atoms), and X is a (CR2)m- group (m means 0 to 5); ].

The invention furthermore relates to a process for the preparation of the compounds of general formula I as defined above, as well as to pharmaceutical preparations containing them as active substance.

The method comprises: a) the general formula ■ (wherein U, V, W and X have the abovementioned meanings, is alkyl, R8 is alkyl having 1 to 5 carbon atoms, and R9 is optionally substituted alkyl having up to 20 carbon atoms, or
aryl or cycloalkyl with 5 to 5 carbon atoms, in which case one CH2 group may be replaced by an oxygen atom, by reverse Dieckmann condensation (Re t ro-Die
ck-mannkondensat 1on), and the general formula
and U, V, W and X have the same meanings as in formula together, the U
, V , W and and reduce it to give the general formula I
b (wherein R1 and R2 each represent hydrogen or hydroxy, R1 and R2 are different, and U,
V, W and X have the meanings given above), and the reaction product is optionally converted into the free acid or salt.

U means above all a polymethylene chain with up to 3 single CH2 groups, but among the other groups mentioned in the definition of U R3 or R4 means an alkyl residue with up to 3 carbon atoms; Preferably something that does.

The groups X, W and ■ together form inter alia an optionally branched chain with up to 10 members.

When (2) represents a phenylene or phenoxy residue, the remaining molecular moieties may be located in the o-, m- or p-position relative to each other.

The starting compound of formula (1) used in method a is described, for example, in Japanese Patent Application No. 70076/1982, and can be produced by the method described therein.

That is, for example, a compound having the formula ■a (wherein R7 and R9 have the meanings described for the formula ■) is prepared in a neutral solvent in the presence of a base with the formula nb (wherein U , V , W, X and R8 have the meanings given for formula (1).

The reaction is conveniently carried out in an inert atmosphere at temperatures between room temperature and 140°C.

Benzene, toluene or xylene is preferred as the neutral solvent.

The base used is inter alia anhydrous sodium ethylate or potassium tert-butylade.

Compounds of formula 11a may be prepared by the method described in Belgian Patent No. 766.521.

The reverse Dieckmann condensation is carried out in a manner known per se (cf. Belgian Patent No. 766.521), inter alia in the presence of 1 to 1.5 mol of alkali alcoholade in the alcohol, at temperatures from room temperature to 150°C. The test is carried out in an inert gas atmosphere for a period of time.

The reaction product having the general formula (II) is subjected to alkaline saponification, decarboxylation and acidic ether decomposition by methods known per se, either immediately by customary work-up or after chromatographic purification (see Belgian Patent No. 766, cited above).
521 specification).

The compounds of the general formula (1) are prepared as follows by methods known per se (see Belgian Patent No. 766.521).

That is, 1 to 1 of the alkali alcoholade in alcohol, especially sodium ethylate in ethyl alcohol.
A compound of the general formula (1) obtained based on Japanese Patent Application No. 1970-70076 was dissolved in a 1.5 mol anhydrous solution, and the solution was heated for 20 to 150 hours for 1 to 16 hours while excluding oxygen and moisture.
Stir at a temperature of °C.

The reaction time and reaction temperature depend on the reactivity of the compound (1) used, but generally the reaction is completed after 2 to 6 hours at a temperature of 50 to 90°C.

150 in benzene or xylene solution as the case may be
The reaction is terminated by heating to a temperature of up to .degree.

It is then carefully acidified, preferably with acid salts of polybasic acids, and worked up in customary manner.

Purification of the compound having the general formula (1) is carried out by chromatography on silica gel.

Advantageous variants of the process for preparing compounds having the general formula Ia include the following methods.

That is, an unpurified compound having the general formula (■) is directly saponified using an alcoholic aqueous solution of a base, the precipitated dicarboxylic acid is acidified with a dilute acid, and then isolated from the aqueous phase using an organic solvent, and benzene or 80-110 in toluene
Decarboxylation in a manner customary for β-keto acids by heating for 1 to 4 hours at 10°C is followed by removal of the protecting group for the alcohol function at position 15, e.g. It is cleaved by hydrolysis using an aqueous solution of an organic acid such as

The crude, non-naturally occurring brostanic acid analogues of the general formula Ia thus obtained can be purified, for example, by chromatography on silica gel using a cyclohexane/acetate mixture with the addition of acetic acid.

Although this gives rise to racemates which can be used as such, compounds of general formula Ia can be resolved into their optical antipodes by forming salts with optically active bases.

From compounds of general formula Ia according to method b) as described above, compounds of general formula I
The reduction to the compound b is carried out in a manner known per se with a metal hydride complex, conveniently a metal poranate such as hydrogenated zinc boronate in an organic solvent or in an aqueous-organic phase or in an alcoholic solution. Hydrogenation is carried out using an alkali boranate such as sodium boronate.

The reaction products are worked up by customary methods and purified by chromatography.

The compounds thus obtained yield epimers for the 9-position, which can be used directly or separated into the desired epimers by separation methods customary for stereoisomers, for example by thin layer chromatography.

If a racemate of the general formula IIa is used as a starting material, a racemate of the general formula Ib (positions 8 and 12)
) is obtained.

Enantiomer separation can then be accomplished by salt formation using an optical base.

The conversion of the free acid into the physiologically acceptable salt is carried out by methods known per se.

Salts include, for example, alkali salts or also triethanolammonium salts or benzylammonium salts.

Compounds of general formula I are sometimes designated as racemic brostanoic acids (in terms of nomenclature, inter alia N,
Andersen [Annals of the New York Academy of Sciences]
of the New York Academy
5sciences) Volume 180, Prostagi Engines, page 14).

In addition to the compounds described in the Examples below, for example, the following compounds can be produced by the method of the present invention.

9.15α-dihydroxy-6-methyl-3-oxa-
5-cis-13-trans-prostadienoic acid, 9.15α-dihydroxy-5-methyl-3-oxa-
5,13-trans-prostadienoic acid, 7-ethyl-
15α-hydroxy-9-oxo-13-trans-prostenic acid, 6.6-diethyl-15α-hydroxy-9-oxo-
13-trans-prostenic acid, 9.15α-dihydroxy-4,4-dimethyl-13-
Trans-prostenic acid, 9.15α-dihydroxy-2,2-dimethyl-3-oxa-13-trans-prostenic acid.

The compounds of general formula I are superior to their natural products in terms of their distinct pharmacological action.

Compounds of the general formula 1a are particularly distinguished, for example, by having a pronounced proconvulsant effect.

For example, 15α-hydroxy-9-oxo-13-trans-prostenic acid (Example 4, general formula I a , U'
= (CH2)5, ■ and W = single bond and X = (C
H2) 2nd place in m, m=0), then 3.4, 5
When one CH2 group is introduced at the 1st position (Examples 5, 6, 7)
, 8), the convulsive activity first decreases due to the methyl side chain at position 21, and increases again when reaching the 5-methyl compound.

15α-hydroxy-5-methyl-9-oxo-13-
Trans-prostenic acid (Example 5) showed good proconvulsant activity and 15α-hydroxy-9-oxo-13-
It shows lower blood pressure lowering effect and better bronchodilation effect compared to trans-prostenic acid.

Pharmacological efficacy is evaluated by the following tests. 31) Effect on smooth muscle (Vane, British Journal of Pharmacology and Chemotherapy (B.
r.J., Pharmac, Chemother, ) 12
vol., p. 344, 1957) Wistar rats of both sexes weighing 200 to 220 g are used as experimental animals.

The animal is killed with a blow to the neck and the stomach is quickly removed and placed in a Pemilial dish containing pre-warmed Krebs' solution.

The fundus, which is easily distinguished from the pyloric region by its gray appearance, is separated and incised longitudinally by making a longitudinal incision.

Then make a horizontal cut facing left.

This forms a stripe suitable for suspension in the organ bath.

The organ bath contains conventional Krebs' solution, the temperature of which is maintained at 37°C, 95% O2 and 5% CO2.
It is foamed by a mixture of 2.

A writing lever whose load is 1 g is used to transmit to the kymograph the contraction caused by adding the substance to be tested to the organ bath.

The shrinkage that occurs after the addition of the substance to be tested is used as the experimental standard.

The magnitude of the effect is investigated by comparing the shrinkage that occurs after addition of 600 n97m1PGA2.

From the values expressed in % relative to the comparative preparations it is possible to construct a dose-effect curve, from which the average effective dose can be determined.

All substances are provided as neat solutions in absolute alcohol;
It is further diluted with phosphate buffer (pH=7.4) to its final concentration.

2) Konzett-Ros
Testing of intravenously administered preparations for bronchospasmodic antispasmodic action by the bronchial antispasmodic action method.
exp, Path, Pharmakol.

This corresponds to the description in Volume 195, page 71 (1940).

A male white guinea pig weighing 400 to 500 g is used as the experimental animal, and is anesthetized using hexobarbital and urethane.

All formulations to be administered are prepared in phosphate buffer ((pH=
7.4) and administered in a volume of 0.1 ml.

To record physiological or pharmacological effects, the volume of air taken up by the lungs is measured when the maximum inflation pressure is held constant and an overpressure pulse provides a constant volume.

Volume changes in the trachea are here manifested in an increase or decrease in the amount of air absorbed into the lungs under a given inflation pressure.

Acetylcholine or histamine is injected intravenously to induce severe bronchial spasm.

An amount of stimulant is selected which results in a reduction in the inhalation capacity of the lungs by approximately 70-80%.

The substance to be tested is administered intravenously into the jugular vein.

Thirty seconds later a known amount of the stimulant is injected again.

The mean inhibition can be read off from a graph or from a dose-effect curve generated by regression analysis.

3) Test of circulatory effect The blood pressure lowering effect was determined by Kannegie-s
ser) and Lee's ``Nature''
ure), Volume 229 (1971).

Cats of both sexes weighing 20 to 30 kg are used as experimental animals.

The above experimental animals were placed in a 0.9% NaCl solution for 1.7-2.
5■/kg/ with 8mg/ml bendoparvicool
Anesthetized Ventolinium (Anso) as a continuous infusion for hours
Lysen, May & Baker) 10 kg/animal perform intraperitoneal oil treatment.

Application of the test substance is carried out through the jugular vein.

Blood pressure is measured in the carotid artery and recorded on a multitube recorder using a Statham manometer.

The maximum change in systolic and diastolic blood pressure is Measured in mmHg.

All test preparations were provided as stock solutions in absolute alcohol and immediately added to phosphate buffer (pH=
7.4) to the final concentration.

Compounds that exhibit good bronchodilator action with a weak blood pressure effect are of great value when used in medicine, for example in the treatment of acute asthma attacks.

In the following Table 1, the campogenic, antihypertensive and bronchodilatory effects of several compounds included in the present invention are shown in comparison with each other.

The alcohols of general formula Ib are distinguished by a good campogenic effect, for example on the isolated The rat gastric ED5o is 3.1/μI/ml.

A further advantage of the compounds of the invention is their relatively greater acid and base stability relative to the E- and F-series prostaglandins.

The invention further relates to the production of compounds which differ from their natural analogues in their pharmacological properties and which are superior to natural prostaglandins for the treatment of diseases.

Examples of medicinal uses include bronchial asthma, hypertension,
Edema may occur.

The compounds according to the invention having the general formula I can be used in the form of their aqueous solutions or suspensions, optionally also as salts with organic or inorganic bases, or furthermore for example with monohydric or polyhydric alcohols, dimethylsulfoxide or dimethylformamide or N, as a solution in a pharmacologically non-hazardous organic solvent such as N-dimethylacetamide.
It can also be used in the presence of pharmacologically non-hazardous polymeric carriers, such as polyvinylpyrrolidone.

Preparations include conventional galenic infusions or injections and tablets.

Still other use forms include creams, emulsions, suppositories or aerosols.

For oral use forms, the active compounds are mixed, inter alia, with compounds known per se and brought into suitable dosage forms, eg tablets, dragees or insert capsules, by methods known per se.

As inert carriers, for example magnesium carbonate, lactose or corn starch can be used with addition of other substances such as, for example, magnesium stearate.

At that time, the formulation is as dry granules or wet granules.
Approximately 100 mg to 10 mg per day is contemplated.

- a dosage unit containing, inter alia, 10 r of the compound according to the invention;
Contains n9-1■.

These compounds may be used alone or in conjunction with other pharmacological agents, such as diuretics or antihypertensives or anti-asthmatic agents.

Example 1 Racemic 15α-hydroxy-9-oxo-1,5-inter-p-phenylene-2,3,4-trinor-13-
trans-prostenic acid a racemic 10-ethoxycarbonyl-9-oxo-1
5α-tetrahydropyranyloxy-1,5-inter-p-phenylene-2,3,4-trinor-13-trans-prostenic acid ethyl ester (5R3,3”'SR) -1-(3'-(4 ″-ethoxycarbonylphenyl)-propyl]-2-oxo-
5-(3″′-(2″-tetrahydropyranyloxy)
1.6 g (3.5 mmol) of -trans-1'-octenyltwocyclopentanecarboxylic acid ethyl ester and 4.15 ml of an anhydrous IN-solution of sodium ethylate in ethanol are heated to the boil for 6 hours (bath temperature 85 - 90
℃).

Thin layer chromatographic analysis of the reaction mixture shows that all starting material has been consumed (using A1203-plates and cyclohexane/ether 1:1 as developer).

After addition of 2 mm1 of dry toluene, the ethanol is evaporated and the mixture is cooled to -10°C.

Add 4.5 ml of 2N-NaH2PO4 aqueous solution to the cooled solution while stirring.

The organic phase is further washed with water and dried over MgSO4.

Evaporation gave 1.53 g of crude product, which was dissolved in 120 g of silica gel (Merck, 70-230 mesh AS).
TM) chromatography on top.

Eluent dichlorohexane/acetic acid ester/triethylamine 90:10:1 200ml cyclohexane/
Acetate ester/triethylamine 80:20:
1. Take a fraction consisting of 900ml and 18ml.

870 mg of oily product are obtained from fractions 52-130.

Rf=0.57 (cyclohexane/acetic acid ester/glacial acetic acid 40:60:1) NMR: 7.65 ppm (4 days 1 quartet), 5.5 p
pm (2H), 4.65 ppm (1H), 4.5-3
．． 4ppm b racemic 15α-hydroxy-9-oxo-1,5-
inter-p-phenylene-2,3゜4-toIJ true 13-trans-prostenic acid racemic 10-ethoxycarbonyl-9-oxo-15α-tetrahydropyranyloxy-1゜5-inter-p-phenylene-2 ,3
, 710 μm (1.3 mmol, mol) of 4-trinor-13-trans-prostenic acid ethyl ester in methanol 2
0 ml and 14 ml of 0.6N caustic soda and heated to 60-65° C. with stirring for 6 hours.

The methanol is evaporated in vacuo in a rotary evaporator and the remaining aqueous solution is washed twice with ether and then saturated with NaCl.

The ether is layered and acidified to pH 1-2 using 1N hydrochloric acid while stirring under cooling.

The aqueous phase is extracted three more times with ether and the combined organic phases are washed once with water and dried over anhydrous Na2S04.

After evaporation of the ether, 620 ml of oil is obtained.

Add this to 7ml of ethanol and 5ml of 2% oxalic acid aqueous solution.
Heat to 60-65° C. with IL1 for 1 hour.

After removing the ethanol in vacuo, it is partitioned between ether and water and the organic phase is dried over Mg5O and evaporated.

The oily residue was dissolved in 40 g of silica gel (Merck, 70-2
Chromatography is carried out using cyclohexane/acetic acid ester/glacial acetic acid 60:40:1 on a 30 mesh (ASTM) and 4 ml fractions are collected.

Crystalline product after evaporation from fractions 57-76 260
rn9 is obtained.

m. 9.110-113°C Rf=0.29 (cyclohexane/acetic acid ester/glacial acetic acid 40:60:1) NMR: '7.6.5 ppm (4H, quartet), 6.
85 ppm (2H), 5.6 ppm (2H), 4.
1 ppm (IH) Example 2 Racemic 15α-hydroxy-3-methyl-9-oxo-
4,5,6-t-reflu 13-trans-prostenic acid a racemic 10-ethoxycarbonyl-3-methyl-9
-oxo-15αtetrahydropyranyloxy-4,5
,6-dolinol-13-trans-prostenic acid ethyl ester (5R8,3'SR) -1-(3'-ethoxycarbonyl-2'-methylpropyl)-2-oxo-
2.5 g (5 mmol) of 5-(3'-(2-tetrahydropyranyloxy)-trans-1''-octenyl]-cyclopencunecarboxylic acid ethyl ester was dissolved in 0.93 N-sodium ethylate sulfur in absolute ethanol. liquid 5.8
ml (5.4 mmol) for 6 hours at 80° C., and after addition of 25 ml of anhydrous toluene, the solvent is distilled off to a boiling point of 110° C. (under normal pressure).

Cool this solution to 0°C, add 10 ml of 25% sodium dihydrogen phosphate solution and 20 ml of ice-cooled saturated sodium chloride solution.
Add Ll and shake 4 times with 100 ml of diethyl ether.

The combined ether extracts are washed three times with 20 ml of H2O, dried over Na2SO4 and the solvent is evaporated in vacuo.

The residue is chromatographed on Merck silica gel (column packing height 22 cm, diameter 3.2 cm) and separated into 310 fractions, eluting with the following solvent mixture:

Fractions 131-159 contain 184 mg of slightly contaminated material and fractions 160-310 contain pure racemic 10-ethoxycarbonyl-3-methyl-9-
Oxo-15α-tetrahydropyranyloxy-4,5
, 6-dolinol-13-trans-prostenic acid ethyl ester.

Racemic 3-methyl-9-oxo-15α-tetrahydropyranyloxy-4,5,6-dolinol-13-trans-prostenic acid 1.26 g of the above ester in 20 ml of methanol
N-NaOH5, stirred with 1 ml at room temperature for 48 h and at 50 °C for 5 h under argon,
The solvent was distilled off in vacuo and the residue was dissolved in 20ml of saturated NaC4 solution.
and acidified to pH 1 using 2N HCl.
Extract 3 times with 0 ml of diethyl ether.

The combined ether extracts were washed until neutral and Na
2 Yellow oil 1 by drying with S04 and concentrating
．． 1851 is obtained.

This is heated under reflux in 50 ml of benzene for 1 hour and the solvent is removed in vacuo.

C, racemic 15α-hydroxy-3-methyl-9-oxo-4,5,6-dolinol-13-trans-prostenic acid The residue of Example 2b was mixed with 18 ml of a 2% oxalic acid solution in 30 ml of methanol for 2 hours at 50°C. and methanol is distilled off in vacuo.

The aqueous residue was extracted three times with 150 ml of diethyl ether, the combined ether extracts were washed twice with 20 ml of water and N
Dry over a2SO4 and concentrate in vacuo.

1.023 g of residue is obtained.

This brownish oil is chromatographed on Merck silica gel (column packing height 18 cm, diameter 2.2 cm).

Fractions 246-255 contain slightly contaminated 134μ, and fractions 256-350 contain pure racemic 15α-hydroxy-3-methyl-9-oxo-
Contains 303 mg of 4,5,6-dolinol-13-trans-prostenic acid.

Rf on Merck silica gel plate (cyclohexane/acetic acid ester/glacial acetic acid 60:40:1) = 0
．． 1 NMR (in CDC13) - heavy line 7.55 ppm (2H)
Multiplet 5.4~5.6 ppm (2H) Multiplet 4~
4.15ppm (IH) Example 3 Racemic 15α-hydroxy-3-oxa-9-oxo-
513-4 Lance-prostadienoic acid (5R8,3"5R)-1-(6'-methoxycarbonyl-5'-oxa-trans-/-hexenyl)-2-
1.76 g (3.5 mmol) of oxo-5-[3"-(2"-tetrahydropyranyloxy)-trans-1"-octenylcycyclopentanecarboxylic acid ethyl ester was added to a freshly prepared 1N solution under argon. - with 3.6 ml (3°6 mmol) of sodium ethylate solution
Heat to 80° C. for an hour.

This solution was added to 20 m of an ice-cold NaH2Po4 solution at 0°C.
1, shaken with 500 ml of diethyl ether, washed with water, dried and concentrated.

1.8 g of clear oil was obtained, which was mixed with 16 ml of methanol.
Dissolve in solution and stir with 16 ml of 0.6N NaOH at room temperature for 3.5 hours.

The solution was concentrated under reduced pressure and adjusted to pH 2 using 2N-HCl.
Extract twice with 200 ml each of diethyl ether, wash with water, dry and concentrate.

1.6 g of yellow oil are obtained.

Puff this for 4 puffs and 30 puffs.

The benzene is distilled off in vacuo and the residue is dissolved in 25 ml of ethanol and stirred with 25 ml of 2% oxalic acid solution for 6 hours at room temperature.

The ethanol is distilled off under reduced pressure, the aqueous solution is extracted twice with 200 ml each of diethyl ether, and the ether phase is washed, dried and concentrated.

1.53 g of crude product are obtained.

This was subjected to chromatography on 50 g of Merck's silica gel.

Purified substance 690■ Rf =0.1 8 (silica gel, cyclohexane/
Acetate ester 70:35) NMR (CDC13): 6.1 ppm (2H1-double line)
5, 5-5 near ppm (2H1 multiplet) 3,9
~4.4 ppm (5Hl-multiplet and multiplet) Example 4 Racemic 15α-hydroxy-9-oxo-13-trans-prostenic acid (5R8,3"5R)-1-('6'-ethoxy carbonylhexyl)-2-oxo-5-[3″-(2///
2.5 g (4.8 mmol) of a 1.05 N solution of sodium ethyl ester in absolute ethanol (4.7 ml)
(50 mmol) and heated to 80°C for 4 hours, then 15ml of anhydrous toluene was added and the solvent was distilled off until the boiling point at normal pressure reached 110°C.

Work-up as described in Example 3 gives 2.5 g of oily crude product.

This was added in 50 ml of ethanol to 0.0 ml of ethanol. 6 N - N a
Stir under argon for 4 hours with 9 ml of OH.

Post-processing is carried out in the same manner as in Example 3.

2.2 g of oil are obtained. This is heated at reflux for 2 hours in 30 ml of anhydrous benzene without further purification.

The solvent was concentrated in vacuo and the residue was diluted with 2% in 50 ml of ethanol.
Stir with 28 ml of oxalic acid aqueous solution at room temperature for 8 hours,
Crude product after the same work-up as in Example 3: 1.95
g is obtained.

From this crude product, pure 15α-hydroxy-9-oxo-13-trans-prostenic acid 54 is obtained after chromatography on silica gel, elution being carried out with cyclohexane/acetic acid ester/glacial acetic acid 70:30:1.
0 mg as well as 250 mg of slightly contaminated product are obtained.

NMR (in CDC13): 6.5-6.6 ppm
(-multiple line 2H) 5.5 to 5.7 ppm (multiple line 2H) 4 to 4.3 ppm (multiple line 1H) Crystals having a melting point of 77 to 81°C are obtained by laminating petroleum ether.

Rf=0.1 (cyclohexane/acetic acid ester/glacial acetic acid 60:40:1) Example 5 Racemic 15α-hydroxy-5-methyl-9-oxo-
13-trans/prostenic acid (5R8,3"5R)-1-(6
'-ethoxycarbonyl-3'-methylhexyl)-2
-Oxo-5-(3"-(2"-tetrahydropyranyloxy)-trans-1"-octenyldi-cyclopentanecarboxylic acid ethyl ester) is prepared.

Rf=0.33 (cyclohexane/acetic acid ester/glacial acetic acid 40:60:1) NMH near, 6 ppm (2H), 5.55 ppm (2
H), 4.2 ppm ppm (1H) Example 6 Racemic 15α-hydroxy-4-methyl-9-oxo-
13-trans-prostenic acid (5R8,3″SR)-1-(6′-ethoxycarbonyl-4′-methylhexyl)-2-oxo-5-(3″
-(2”-tetrahydropyranyloxy)-trans-
Obtained in the same manner as in Example 3 from 1"-octenylcycyclopentanecarboxylic acid ethyl ester.

Rf=0.31 (cyclohexane/acetic acid ester/glacial acetic acid 40:60:1) NMR near, 2ppm (2H), 5.6ppm (2H)
.

4.2 ppm (1H) Example 7 Racemic 15α-hydroxy-3-methyl-9-oxo-
13-trans-prostenic acid (5R8,3"SR) -1-(6'-ethoxycarbonyl-5'-methylhexyl)-2-oxo-5-(3
It is obtained in the same manner as in Example 3 from "-(2"-tetrahydropyranyloxy)-trans-1"-octenylcycyclopencunecarboxylic acid ethyl ester.

Rf=0.34 (cyclohexane/acetic acid ester/
Glacial acetic acid 40:60:1) NMR: 6.4 ppm (2H), 5.6 ppm (2H)
H).

4,15 ppm (I H) Example 8 Racemic 15α-hydroxy-2-methyl-9-oxo-
13-trans-prostenic acid (5R8,3"5R)-1-(6'-ethoxycarbonylheptyl)-2-oxo-5-[3"-(2"-tetrahydropyranyloxy)-trans-Y'- It is obtained in the same manner as in Example 3 from octenylcycyclopencune carboxylic acid ethyl ester.

R (-= 0.41 (cyclohexane/acetic acid ester/glacial acetic acid 40:60:1) NMR: 6.75 ppm (2H), 5.6 ppm (2
H).

4.1 ppm (IH) Example 9 Racemic 2-ethyl-15α-hydroxy-9-oxo-
13-trans-prostenic acid (5R8, 3"5R)-1-(2'-ethoxycarbonyl-octyl)-2-oxo-5-[3"-(2"-tetrahydropyranyloxy)-trans-1" - Obtained in the same manner as in Example 3 from octenylcycyclopentanecarboxylic acid ethyl ester.

Rf=0.36 (cyclohexane/acetic acid ester/glacial acetic acid 40:60:1) NMR: 5.6 ppm (2H), 5.4 ppm (2
H).

4.1 ppm (IH) Example 10 Racemic 2-butyl-15α-hydroxy-9-oxo-
13-trans-prostenic acid (5R8,3SR)-1-(6'-ethoxycarbonyldecyl)-2-oxo-5-(3"=(2"-tetrahydropyranyloxy)-trans-1"-octenyl Seacyclopencune carboxylic acid ethyl ester 1.8C
! ? (3.1 mmol) in 3.9 ml of IN-sodium ethylate solution in ethanol as described in Example 3.
After heating to 80° C. for 5 hours and adding 25 rnl of anhydrous toluene, the solvent is evaporated to the boiling point of toluene.

After working up, 1.84 g of crude product are obtained.

Add this to methanol/L/0.5N-NaOH in 20ml
After stirring and working up 20 ml at room temperature for 48 hours and at 60° C. for 72 hours, 685 mg of oil are obtained.

2-Butyl-15α-hydroxy-9-keto-13-trans-
240 μm of protinic acid are obtained.

The NMR in CDCl3 is almost identical to the spectrum of Example 4.

R4=0.17 (cyclohexyl/acetate/glacial acetic acid 60:40:1) Example 11 Racemic 15α-hydroxy-9-oxo-2-true 1
3-trans-prostenic acid a, racemic 10-ethoxycarbonyl-9-oxo-1
5α-tetrahydropyranyloxy-2-true 13-
trans-prostenic acid ethyl ester (5R8, 3″SR) -1-(5′-ethoxycarbonylpentyl)-2-oxo-5-(3″-(2″-tetrahydropyranyloxy)-trans-f/- It is prepared from octenylcycyclopencune carboxylic acid ethyl ester in the same manner as in Example 1a.

Rf=0.23 (cyclohexane/acetic acid ester 85
:15) NMR: 5.6ppm (2H), 4.65ppm (IH
).

4.4-3.3 ppm (7H) b, racemic 15α-hydroxy-9-oxo-2-true 13-trans-prostenic acid racemic 10-ethoxycarbonyl-9-oxo-15α
-Tetrahydropyranyloxy-2-true 13-trans-prostenic acid ethyl ester is prepared analogously to Example 1b.

Rf=0.31 (cyclohexane/acetic acid ester glacial acetic acid 40:60:1) NMR: 6.35 ppm (2H), 5.65 ppm
(2H).

4.2 ppm (IH) Example 12 Racemic 15α-hydroxy-2-methyl-9-oxo-
3-Flu-13-trans-prostenic acid (5R3,3"5R)-1-(5'-ethoxycarbonylhexyl)-2-oxo-5-[3"-(2///-
Tetrahydropyranyloxy)-trans-f/-octenylcycyclopencune carboxylic acid ethyl ester 1
．． 9 g (3.6 mmol) was heated at 80°C for 6 hours with 4 TIL of a 1N sodium ethylate solution in ethanol, and after adding 25 ml of toluene, the solvent was brought to a boiling point of 110°C above normal pressure.
Distill until .

After treatment in the same manner as in Example 3, 1.9 g of oil is obtained.

Saponification, decarboxylation and etherification were carried out under the same conditions as described in Example 3, and after work-up 1.55 g of crude product was obtained, which was chromatographed on silica gel and cyclohexane. Pure racemic 15α-hydroxy-2- by elution with /acetate/glacial acetic acid 60:40:1
374 ml of methyl-9-oxo-3-true 13-trans-prostenic acid are obtained.

The NMR spectrum is almost the same as that in Example 4.

R (= 0.14 (silica gel, cyclohexane/acetic acid ester/glacial acetic acid 60:40:1) Example 13 Racemic 2-ethyl-15α-hydroxy-9-oxo-
3-Flu-13-trans-prostenic acid (5R8,3"SR) -1-(5'-ethoxycarbonyl-heptyl)-2-oxo-5-[3"-(2"'
-Tetrahydropyranyloxy)-trans-1''-octenylcycyclopenconic acid ethyl ester in the same manner as in Example 3.

Rf=0.33 (cyclohexane/acetic acid ester/glacial acetic acid 40:60:1) NMR: 5.65 ppm (2H), 4.2oom (I
H) Example 14 Racemic 2-butyl-15α-hydroxy-9-oxo-
3-True 13-trans-prostenic acid Similarly to Example 3, (5R8,3"5R)-1-(
5'-ethoxycarbonylnonyl)-2-oxo-5 [
1.9 g (3.4 mmol) of 3"-(2"'-tetrahydropyranyloxy)-trans-1"-octenylcycyclopencunecarboxylic acid ethyl ester was added to 1N-
80 for 4 hours with 3.8 ml of sodium ethylate solution
After heating to 0.degree. C. and adding 30 rnl of anhydrous toluene, the solvent is distilled off to a boiling point of 110.degree.

After working up, 1.7 g of viscous oil are obtained.

This is heated to 50 DEG C. for 8 hours with 30 rrLl of methanol and 30 ml of 0.3N caustic soda.

After post-treatment and heating in benzene for 1 hour, the oil was heated to 900mF? is obtained, which is heated to 50 DEG C. for 4 hours with 30 ml of ethanol and 157,711 ml of 2 ml of oxalic acid solution.

After fresh work-up, the crude product 660rn9 was obtained, which was chromatographed on silica gel to give pure racemic 2-butyl-15α-hydroxy-9-oxo-3-true 13-trans-prostenic acid 245 and A further 220 μ of slightly contaminated product are obtained.

The NMR spectrum is almost identical to that obtained in Example 4.

Rf = 0.19 (silica gel, cyclohexane/
Acetate/glacial acetic acid (60:40:1) Example 15 Racemic 15α-hydroxy-9-oxo-2°3-dinol-13-trans-prostenic acid a, racemic 10-carboethoxy-9-oxo-15α- Tetrahydropyranyloxy-2,3-dinol-13-trans-prostenic acid ethyl ester (5R8,3"5R)-1-<4-ethoxycarbonyl-ω-butyl)-2-oxo-5-1:3" −(2”−
Prepared analogously to Example 1a from tetrahydropyranyloxy)-trans-1''-octenylcycyclopencune carboxylic acid ethyl ester.

R (= 0.26 (cyclohexane/acetic acid ester 8
5:15) NMR: 5.6 ppm (2H), 4.7 ppm (I
H).

4, 4.4-3.0ppm b, racemic 15α-hydroxy-9-oxo-2゜3-
Prepared analogously to Example 1b from dinor-13-trans-prostenic acid 10-carboethoxy-9-oxo-15α-tetrahydropyranyloxy-2,3-dinol-13-trans-prostenic acid ethyl ester.

m, p, 72-76°C R4 = 0.30 (cyclohexane/acetic acid ester/glacial acetic acid 40:60:1) NMR: 6.55 ppm (2H), 5.6 ppm (
2H).

4.1 ppm (IH) Example 16 Racemic 15α-hydroxy-2-methyl-9-oxo-
3,4-dinol-13-trans-prostenic acid (5R8,3"5R)-1-(4'-ethoxycarbonylpentyl)-2-oxo-s (3//(2///
Tetrahydropyranyloxy)-trans-,=/-octenylcycyclopencunecarboxylic acid ethyl ester is reacted as in Example 3.

Rf=0.32 (cyclohexane/acetic acid ester/glacial acetic acid 40:60:1) NMR: 5.65 ppm (4H), 4.15 ppm
(IH) Example 17 Racemic 2-ethyl-15α-hydroxy-9-oxo-
3,4-dinol-13-trans-prostenic acid (5R8,3"S'R)-1-(4'-ethoxycarbonylhexyl)-2-oxo-5-[3"-(2"-tetrahydropyranyl oxy)-trans-1″-octenylcycyclopenkune carboxylic acid ethyl ester 1.
94 g (3.7 mmol) are heated to 80 DEG C. for 5 hours with 4.1 ml of a solution of sodium ethylate in ethanol and, after addition of 25 ml of toluene, the solvent is distilled off to a boiling point of 110 DEG C.

A crude yield of 2 g of oil is obtained.

This was mixed with 35m of 0.3N-NaOH in 35ml of methanol.
1 for 2 days at 50.degree. C., worked up and decarboxylated by heating at 80.degree. C. for 1 hour in 30 ml of Pencef as described above.

After working up as described above with 23 ml of a 2% oxalic acid solution in 25 ml of ethanol at room temperature for 10 hours to decompose the tetrahydropyranyl ether protecting group, 1.7 g of a dark oil is obtained.

Chromatography on silica gel and elution with cyclohexane/acetic acid ester/glacial acetic acid 70:30:1 gives 295 ml of a viscous oil.

The NMR spectrum is similar to that of Example 4.

Rf=0.11 (silica gel, cyclohexane/acetic acid ester/glacial acetic acid 60:40:1) Example 18 Racemic 15α-hydroxy-9-oxo-2-homo-1
3-trans-prostenic acid (5R8,3"5R)-1-(7'-ethoxycarbonylheptyl)-2-oxo-5-[3"-(2"-tetrahydropyranyloxy)-trans-1"- octenyl)-cyclopentanecarboxylic acid ethyl ester in the same manner as in Example 3.

Rf=0.28 (cyclohexane/acetic acid ester/glacial acetic acid 40:60:1) NMR: 6.3 ppm (2H), 5.6 ppm (
2H).

4.1 ppm (IH) Example 19 Racemic 15α-hydroxy-3-methyl-4-oxa-
9-Oxo-13-trans-prostenic acid (5R8, 3"SR) -1-(6'-ethoxycarbonyl-5'-methyl-4'-oxahexyl)-2-oxo-5-[3"-( 2''-Tetrahydropyranyloxy)-trans-1''-octenylcucyclopentanecarboxylic acid ethyl ester Kara Prepared similarly to Example 3.

Rf=0.1 (silica gel, cyclohexane/acetic acid ester/glacial acetic acid 30nia 0:1) NMR: 6-6.1 ppm (2H, - heavy line), 5.5-
5.7ppm (2H, multiplet), 3.6-4.4p
pm (4H1 wide signal) Example 20 Racemic 15α-hydroxy-3-oxa-9-oxo-
13-trans-prostenic acid (5R8,3"SR) -1-(6'-methoxycarbonyl-5'-oxahexyl)-2-Jxo-5-[3
It is prepared in the same manner as in Example 3 from "-(2'-tetrahydropyranyloxy)-trans-f-)r')thenylcucyclopencune carboxylic acid ethyl ester.

Rf = 0.1 (silica gel, cyclohexane/acetic acid ester/glacial acetic acid 30N 0:1) NMR (CDCls)' 5.9 ppm (2H1-heavy line).

5.6-5.8 ppm (2H, multiplet), 4-4.2
ppm (3H, singlet with multiplet).

3.4-3.7 ppm (broad signal) Example 21 Racemic 15α-hydroxy-3-oxa-9-oxo-
5-cis-13-trans-prostadienoic acid (5R8,3"SR) -1-(6'-ethoxycarbonyl-5'-oxa-cis-7-hexenyl)-2-oxo-5-[3"-(2'''tetrahydropyranyloxy)-trans-1''-octenylcucyclopentanecarboxylic acid ethyl ester in the same manner as in Example 3.

Rf ~0.25 (acetic acid ester/methanol 70:
35 silica gel) NMR: 6.85 ppm (2H1-heavy line) 5.7-5
．． 9 ppm (4H1 multiplet) 4-4.3 ppm (5
H1-multitet and multiplet) Example 22 Racemic 15α-hydroxy-2-methyl-3-oxa-
9-Oxo-13-trans-prostenic acid (5R8,3"5R)-1-(6'-ethoxycarbonyl-5'-oxaheptyl)-2-oxo-5-[3"
-(2″-tetrahydropyranyloxy)-trans-
It is prepared analogously to Example 3 from 1"-octenyl)-cyclopentanecarboxylic acid ethyl ester.

Rf = O, 13 (silica gel, cyclohexane/acetic acid ester/glacial acetic acid 30nia 0:1) NMR: 6.4 ppm (2H1-heavy line) 5,5-5.
7 ppm (2H1 multiplet) 3.4-4.2 ppm (4
H1 wide signal) Example 23 Racemic 15α-hydroxy-3-oxa9-oxo-2
-homo-5-cis,13-trans-prostadienoic acid (5R8,3"5R)-1-(7'-methoxycarbonyl-5"-oxa-cis-2'-hebutenyl)-2-oxo-5 -(3''-(2''-tetrahydropyranyloxy)trans-1''-octenylcucyclopentanecarboxylic acid ethyl ester) in the same manner as in Example 3.

Rf ~0.15 (silica gel, cyclohexane/acetic acid ester/glacial acetic acid 60:40:1) NMR: 6.95 ppm (2H, - heavy line) 5,4
~5.7 ppm (4H, multiplet) 3.9~4.4 ppm (5H1 multiplet) Example 24 Racemic 15α-hydroxy-9-oxo-4°7-inter-o-phenylene-5,6-dinol -13-trans-prostenic acid (5R8,3'5R)-1-(2'-(3''-ethoxycarbonylpropyl)-benzyl)-2-oxo-5-
Produced in the same manner as in Example 3 from (3'-(2''-tetrahydropyranyloxy)-trans-1''-octenylcycyclopencunecarboxylic acid ethyl ester.

R (=0.26 (cyclohexane/acetic acid ester/glacial acetic acid 40:60:1) NMR: 7.1 ppm (4H), 6.7 ppm (2
H).

5.54 ppm (2H) Example 25 Racemic 15α-hydroxy-9-oxo-3゜7-inter-p-phenylene-4,5,6-dolinol-(5R8,3'''5R)-1-(4'-(2''-ethoxycarbonylethyl)-penzylco-2-;tt-sos
(3/// (2////-tetrahydropyranyloxy)-trans-1"-octenylcycyclopencune carboxylic acid ethyl ester in the same manner as in Example 3.

R (= 0.30 (cyclohexane/acetic acid ester/
Glacial acetic acid 40:60:1) NMR: 7.1 ppm (4H), 6.8 ppm (2
H).

5.5 ppm (2H), 4.05 ppm (IH) Example 26 Racemic 15α-hydroxy-9-oxo-1.

7-inter-p-phenylene-2,3,4,5.

6-pentanol-13-trans-prostenic acid (5R8,3″5R)-1-(4′-ethoxycarbonylbenzyl)-2-oxo-5-[3″-(2#-tetrahydropyranyloxy)-trans- Y'-octenyl)-cyclopentanecarboxylic acid ethyl ester is prepared analogously to Example 3.

m, p, 106-107°C Rf ~0.30 (cyclohexane/acetic acid ester/
Glacial acetic acid 40:60:1) NMR: 7.65 ppm (4R1 quartet), 6.
7 ppm (2H), 5.55 ppm (2H), 4.0
5ppm (IH), 2.97ppm (2H) Example 2
7 Racemic 15α-hydroxy-5-oxa-9-oxo-
15-inter-p-phenylene-2,3,4-4linol-13-trans-prostenoic acid (5R8,3"5R)-1-(2'-(4"-ethoxycarbonylphenoxy)-ethyl]-2- Oxo-s
Produced in the same manner as in Example 3 from (3/// 2//"-tetrahydropyranyloxy)-trans-1"-octenylcycyclopencune carboxylic acid ethyl ester.

R4=0.35 (cyclohexane/acetic acid ester/glacial acetic acid 40:60:1) NMR: 7.45 ppm (4H, quartet), 6
．． 3 ppm (2H), 5.65 ppm (2H), 4.
15 ppm (3H) Example 28 Racemic 1,7-inter-(2,5-furylidene)-1
5α-hydroxy-9-oxo-2.

3,4,5.6-pentanol-13-trans-prostenic acid (5R8, 3"5R)-1-(5'-ethoxycarbonylfurfuryl)-2-oxo-5-[3"-2"'-tetrahydro It is obtained in the same manner as in Example 3 from pyranyloxy)-trans-1"-octenyl]cyclopentanecarboxylic acid ethyl ester.

R4=0.13 (silica gel, cyclohexane/acetic acid ester/glacial acetic acid 30nia 0:1) NMR (CDCI!3): 7.1-7.3 ppm (I
H doublet) 6.5ppm (2H, - doublet) 6.2ppm (1H? doublet) 5.5~5.7ppm (2R1 multiplet) 4~4.1 ppm (IH1 multiplet) Examples 29 Racemic 9,15α-dihydroxy-3-oxa-5,1
3-trans-prostadienoic acid A and 140 μl of racemic 15α-hydroxy-3-oxa-9-oxo-5,13-trans-prostadienoic acid were dissolved in 20 ml of methanol and hydrogenated three times over 1.5 hours. Add 150 cm of sodium chloride.

The reaction solution was adjusted to pH 7 using glacial acetic acid, the solvent was distilled off in vacuo and the residue was diluted to pH 1 with 2N-HC1 in 10 ml of water.
Acidify and extract three times with 100 ml each of diethyl ether.

The combined ether extracts are washed with water, dried over sodium sulfate and the solvent is removed in vacuo.

The reaction product (140■) is shown to be a mixture of two epimers regarding the position of the 91-hydroxyl group.

The silica gel-promoting epimer (fraction A) is obtained in pure form by chromatography on 4 g of Merck silica gel.

By using cyclohexane/acetate ester 1:9200 mA, A) 30 mg of Rf = 0.45 (silica gel, acetate ester/methanol 70:35) were eluted, and by using 200 mrLl of acetate ester/methanol 8:2 B) DC 4 with 2 spots (mixture of both epimers) inside
4■ is eluted.

Rf=0.45 (silica gel, acetate ester/R(
-0,39 methanol 70:35) NMR fraction A: 5.5-5.8 ppm (
4H.

multiplet) 4.7 ppm (3H1-multiplet) 4-4.2 ppm (6H1-multiplet and multiplet), NMR fraction B: 5.5-5.8 ppm
(4H1 multiplet) 5.2 ppm (3H1 multiplet) 4, to 4.1 ppm (6H1 multiplet and multiplet) Example 30 Racemic 9,15α-dihydroxy-2,3-dinol-1
110 μ (0.28 mmol) of racemic 15α-hydroxy-9-oxo-2,3-dinol-13-trans-prostenic acid in 5 ml of 3-trans-prostenic acid inpropatol was added with 130 μ of sodium borohydride. Divide into small amounts and add (hydrogen generation).

- After standing overnight, evaporate in vacuo at a bath temperature of 30° C. and mix the residue with 201 rLl of ether and 107 rLl of saturated sodium chloride solution.

While stirring under cooling, carefully add 1N-HC4 to adjust the pH.
Acidify to 2.

The aqueous phase is further extracted twice with ether and the combined organic phases are washed with saturated sodium chloride solution, dried and concentrated.

The residue (115rn9) is chromatographed upstream of St 0210 g.

Cyclohexane/acetic acid ester/glacial acetic acid 40:60:1 is used as the eluent.

The isomer that develops first has an Rf value of 0.20 (cyclohexane/acetate/glacial acetic acid 40:60:1), and the one that develops later has an Rf value of 0.17 with the same developer.

NMR (isomer mixture): 5.5 ppm (2H1 multiplet), 5.3 ppm (2H, - multiplet), 4.1 ppm (
Example 31 Racemic 9,15α-dihydroxy-1,5-inter-
p-phenylene-2,3,4-trinor-13-trans-prostenic acid racemic 15α-hydroxy-9-oxo-1°5-inter-p-phenylene-2,3,4-trinor-13-
Obtained in the same manner as in Example 29 from trans-prostenic acid.

Isomer that develops more rapidly Rf = 0.23 (cyclohexane/acetic acid ester/glacial acetic acid 40:60:1) NMR: 7.6 pp pm (4H, A2B2-type)
, 5.5ppm (2H), 4.4-3.9ppm (5
H).

More gradually developing isomers m, p, 124-124 °C R (= 0.19 (cyclohexane/acetate/
Glacial acetic acid 40:60:1) NMR: 7.6 ppm (4H, A2B-J), 5.4
5 ppm (2H), 4.3-3.7 ppm (5H) Example 32 Racemic 915α-dihydroxy-3-oxo-5-cis 13-trans-prostadienoic acid Racemic 15α-hydroxy-3
-oxa-9-oxo-5-cis-13-trans-prostadienoic acid 1501nf/ to racemic 9,15α-
82 ml of dihydroxy-3-oxiftha-5-cis, 13-trans-prostadienoic acid are obtained.

Rf=0.43 (silica gel, acetate/methanol 70:35) NMR (CDC13): 5.4-5.7 ppm (4
H, multiplet) 5 ppm (3H1-multiplet) 3.9-4.3 ppm (6H1-multiplet and multiplet) Example 33 Racemic 9,15α-dihydroxy-2-methyl-3-true 13-trans- Prostenic Acid Example 29 to prepare racemic 15α-hydroxy-2-methyl-9-oxo-3-true 13-trans-prostenic acid from 70 μl to racemic 9° 15α-dihydroxy-2-methyl-3-
56 μl of true 13-trans-prostenic acid are obtained.

Rf ~0.07 (Silica gel, cyclohexane/acetic acid ester/glacial acetic acid 60:40:1) NMR (cDc13): 5.4-5.7 ppm (2H
, multiplet) 5.0 ppm (3H1-multiplet) 3.9-4.3 ppm (2H1 wide signal) Example 34 Racemic 2-ethyl-9,15α-dihydroxy-3,4
-Dinol-13-trans-prostenic acid In the same manner as in Example 29, from 70 mg of racemic 2-ethyl-15α-hydroxy-9-oxo-3,4-dinol-13-trans-prostenic acid, racemic 2-ethyl-9,
40 μ of 15α-dihydroxy-3°4-dinol-13-trans-prostenic acid are obtained.

Rf=0.07 (silica gel, cyclohexane/acetic acid ester/glacial acetic acid 60:40:1) NMR (CDC13): 5.4-5.7 ppm (2H
1 multiplet) 5.0 ppm (3H1-multiplet) 3.9-4.3 ppm (2H, broad signal) Example 35 Racemic 9,15α-dihydroxy-3-oxa-2-homo-5-cis, 13-trans-prostenic acid racemic 15α-hydroxy-3-oxa-9-oxo-
Obtained in the same manner as in Example 29 from 2-homo-5-cis, 13-trans-prostenic acid.

R (= 0.55 (silica gel, acetate/methanol 70:35) NMR (CDC13): 5.4-5.7 ppm (4H1
Multiplet) 5.0 ppm (3H, - multiplet) 3.9-4.3 ppm (6H1 multiplet) Example 36 Racemic 15α-hydroxy-5-methyl-9-oxo-
5-trans-13-trans-prostadienoic acid (5R8,3"SR) -1-(6'-ethoxycarbonyl-3'-methyl-trans-2'-hexenyl)-
2-oxo-5-[3"-(2''-tetrahydropyranyloxy)-trans-Y'-octenylcyclopentanecarboxylic acid ethyl ester obtained in the same manner as in Example 5.

NMR (CDC13): 6.2 ppm (2H), 5.
6 ppm (2H), 5.1 ppm (IH), 4.1
ppm (IH) Example 37 Racemic 9,15α-dihydroxy-5-methyl-13-
4 lance-prostenic acid racemic 15α-hydroxy-5-methyl-9-oxo-
Obtained in the same manner as in Example 30 from 13-trans-prostenic acid.

NMR (CDC73): 5.5 ppm (5H), 4
．． 2 ppm (2H) Example 38 Racemic 15α-hydroxy-6-methyl-9-oxo-
13-trans-prostenic acid (5R8,3"5R)-1-(6'-ethoxycarbonyl-2'-methyl-hexyl)-2-oxo-5[3"
-(l-tetrahydropyranyloxy)-trans-1
“-Octenylcycyclopentanecarboxylic acid ethyl ester obtained in the same manner as in Example 3.

The Rf values and NMR spectra are virtually identical to those described in Example 5.

Example 39 Racemic 15α-hydroxy-4-ethyl-9-oxo-
13-trans-prostenic acid (5R8, 3"5R)-1-(6'-ethoxycarbonyl-4'-ethyl-hexyl)-2-oxo-5-(3
It is obtained in the same manner as in Example 3 from "-(2'/-tetrahydropyranyloxy)-trans-1"-octenylcycyclopentanecarboxylic acid ethyl ester.

Rf=0.35 (cyclohexane/acetic acid ester/glacial acetic acid 40:60:1) Example 40 Racemic 15α-hydroxy-5-ethyl-9-oxo-
13-trans-prostenic acid (5R8,3″SR) -1-(6'-ethoxycarbonyl-3'-ethyl-hexyl)-2-oxo-5-(
It is obtained in the same manner as in Example 3 from 3''-(2''-tetrahydropyranyloxy)-trans-1''-octenylcucyclopencune carboxylic acid ethyl ester.

NMR (CDC13): 6.3 ppm (2H), 5.6
ppm (2H), 4.1 ppm (IH) Example 41 Racemic 15α-hydroxy-6-ethyl-9-oxo-
13-trans-prostenic acid (5R8,3″5R)-1-(6′-ethoxycarbonyl-2′-ethyl-hexyl)-2-oxo-5-[3
It is obtained in the same manner as in Example 3 from ``-(2'(tetrahydropyranyloxy)-trans-1''-octenylcucyclopencune carboxylic acid ethyl ester).

Rf=0.32 (cyclohexane/acetic acid ester/
Glacial acetic acid 40:60:1) Example 42 Racemic 15α-hydroxy-9-oxo-4-t44-
1,4-inter-o-phenylene-23-dinol-1
3-trans-prostenic acid (5R8, 3"SR) -1-(3'-(2"-ethoxycarbonylphenoxy)-propyl-2-oxo-5(3/// (2////-tetrahydro It is obtained in the same manner as in Example 3 from pyranyloxy)-trans-1''-octenylcucyclopencune carboxylic acid ethyl ester.

NMR (CDC13): 6.8-8.2ppm (4R
1 multiplet) 6.4 ppm (2H1-multiplet) 5.7 ppm (2H), 4.2 ppm (3H) Representative examples of the gist and embodiments of the present invention are listed below. This is also included in the mode of carrying out the invention referred to in Article 65-3 of the Patent Law.

1. General formula I [wherein R1 and R2 are jointly oxygen or each hydrogen or hydroxyl group, in which case R1 and R2 are different], U is (CH2)m- group (m is 0 to 5), -C=C- group (R3 and R4 are the same or different and mean hydrogen or alkyl having 1 to 5 carbon atoms) or -C=C- group (R3 and R4 are the same or different and mean hydrogen or alkyl having 1 to 5 carbon atoms, provided that ■ and W are each a single bond and X= (CH2)1 to 3; (both cannot be hydrogen at the same time), and ■ is a single bond, oxygen, or (in the formula, R
3 and R4 are the same or different, meaning hydrogen or alkyl having 1 to 5 carbon atoms), and W is a single bond or a residue of the formula -C-<wherein R5 and R6 are the same or different, meaning hydrogen or an alkyl group having 1 to 5 carbon atoms) and X is a (CH2) m- group (m meaning 0 to 5); ] and its salts with physiologically acceptable inorganic or organic bases.

2, a, General formula ■ [In the formula, U, V, W and X have the above-mentioned meanings, R1 and R2 jointly represent oxygen, and R7 is an alkyl group having 1 to 5 carbon atoms and R8 is an alkyl group having 1 to 5 carbon atoms and R9 is an optionally substituted alkyl group having up to 20 carbon atoms.

aryl group or cycloalkyl group having 5 to 8 carbon atoms (with the exception that one CH2 group may be replaced by an oxygen atom)] is subjected to reverse Dieckmann condensation. and the reaction product having the general formula ■ (in which the residues R1, R2, R7, R8 and R9 and U, V, W and X have the same meanings as in formula ■) is subjected to alkaline saponification, decarboxylation and Upon ether decomposition, the general formula 1a (where R1 and R2 jointly represent oxygen, U,
(V, W and Ib [in the formula, R1 and R2 each represent hydrogen or a hydroxyl group, and in this case R1 and R2 are different],
U, V, W and .

3.15α-hydroxy-3-oxa-9-oxo-1
3-trans-prostenic acid 4.15α-hydroxy-3-oxa-9-oxo-5
, 13-trans-prostadienoic acid 5.15α-hydroxy-3-oxa-9-oxo-5-cis-13-trans-prostadienoic acid 6.15α-hydroxy-5-methyl-9-oxo-1
3-trans-prostenic acid 7.15α-hydroxy-6-methyl-9-oxo-1
A medicament characterized by containing 3-trans-prostenic acid 8, the compound of item 1 above, or a salt thereof as an ingredient.

9. A process for producing a medicament, characterized in that the compound according to item 1 above or a physiologically acceptable salt thereof is formulated into a dosage form, optionally with the addition of auxiliary agents and/or carrier substances.

10. Use of the compound according to item 1 above or a salt thereof as a medicine.

Claims (1)

[Scope of Claims] 1 General formula [wherein R1 and R2 jointly represent oxygen, R7 is an alkyl group having 1 to 5 carbon atoms, and R8 is 1 to 5 carbon atoms] R9 is a tetrahydropyranyl group, U is a (CR2) m- group (m means 0 to 5), and (2) is a single bond, oxygen, or Formula -C-(
In the formula, R3 and R4 are the same or different, meaning 1, hydrogen or alkyl having 1 to 5 carbon atoms), and W is a single bond, or -C- (formula where R5 and R6 are the same or different, meaning hydrogen or alkyl having 1 to 5 carbon atoms), and X is a (CR2) rn- group (m means 0 to 5); ) is subjected to reverse Dieckmann condensation, and the compound having the general formula ■ (wherein residues R1, R2, R7, R8 and R9 and U, V, W and X have the same meanings as in formula ■ by subjecting the reaction product formed by (having) to alkaline saponification, decarboxylation and ether decomposition,
General formula Ia (wherein R1 and R2 jointly represent oxygen and U
, V, W and General formula■ (In the formula, U, V, W, and X have the meanings described above.)
or a method for producing a salt thereof with a physiologically acceptable inorganic or organic base.